Glut1 deficiency syndrome: New and emerging insights into a prototypical brain energy failure disorder

Considering its small size relative to the rest of the body, the mammalian brain has a disproportionately high energy requirement. This energy is supplied to the brain mainly in the form of glucose through the principal cerebral glucose transporter, Glut1. Inactivation of even a single copy of the Glut1 gene, SLC2A1, has dire consequences for the brain, starving cerebral neurons of energy and triggering the debilitating neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). Considering the monogenic nature of Glut1 DS, the disease serves as an excellent paradigm to study the larger family of brain energy failure syndromes. Here we review how studies of Glut1 DS are proving instructive to the brain’s energy needs, focusing first on the requirements, both spatial and temporal of the transporter, second, on proposed mechanisms linking low Glut1 to brain dysfunction and, finally on efforts to treat the disease and thus restore nutritional support to the brain. These studies promise not only to inform mechanisms and treatments for the relatively rare Glut1 DS but also the myriad other conditions involving the Glut1 protein.

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A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain

Disease Models & Mechanisms ◽

10.1242/dmm.038828 ◽

2019 ◽

Vol 12 (9) ◽

pp. dmm038828 ◽

Cited By ~ 1

Author(s):

Tamio Furuse ◽

Hiroshi Mizuma ◽

Yuuki Hirose ◽

Tomoko Kushida ◽

Ikuko Yamada ◽

...

Keyword(s):

Mouse Model ◽

Deficiency Syndrome ◽

Glucose Kinetics ◽

Wake Patterns ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

The Brain ◽

Abnormal Sleep

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Paroxysmal eye–head movements in Glut1 deficiency syndrome

Neurology ◽

10.1212/wnl.0000000000003867 ◽

2017 ◽

Vol 88 (17) ◽

pp. 1666-1673 ◽

Cited By ~ 17

Author(s):

Toni S. Pearson ◽

Roser Pons ◽

Kristin Engelstad ◽

Steven A. Kane ◽

Michael E. Goldberg ◽

...

Keyword(s):

Eye Movements ◽

Eye Movement ◽

Head Movement ◽

Neurodevelopmental Disorder ◽

Deficiency Syndrome ◽

Head Movements ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

History Of ◽

Gaze Saccades

Objective:To describe a characteristic paroxysmal eye–head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS).Methods:We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients.Results:A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually <5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye movements were separated by clear intervals of fixation, usually ranging from 200 to 800 ms. The movements were consistent with eye–head gaze saccades. These movements can be distinguished from opsoclonus by the presence of a clear intermovement fixation interval and the association of a same-direction head movement.Conclusions:Paroxysmal eye–head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder.

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GLUT1 Deficiency Syndrome—Early Treatment Maintains Cognitive Development? (Literature Review and Case Report)

Genes ◽

10.3390/genes12091379 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1379

Author(s):

Ivana Kolic ◽

Jelena Radic Nisevic ◽

Inge Vlasic Cicvaric ◽

Ivona Butorac Ahel ◽

Kristina Lah Tomulic ◽

...

Keyword(s):

Cognitive Development ◽

Motor Development ◽

Glucose Transporter ◽

Genetic Defect ◽

Deficiency Syndrome ◽

Single Nucleotide Variants ◽

Slc2a1 Gene ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

The Brain

Glucose transporter type 1 (GLUT1) is the most important energy carrier of the brain across the blood–brain barrier, and a genetic defect of GLUT1 is known as GLUT1 deficiency syndrome (GLUT1DS). It is characterized by early infantile seizures, developmental delay, microcephaly, ataxia, and various paroxysmal neurological phenomena. In most cases, GLUT1DS is caused by heterozygous single-nucleotide variants (SNVs) in the SLC2A1 gene that provoke complete or severe impairment of the functionality and/or expression of GLUT1 in the brain. Despite the rarity of these diseases, GLUT1DS is of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms, especially if it is started as early as possible. We present a clinical phenotype, biochemical analysis, electroencephalographic and neuropsychological features of an 11-month-old boy with myoclonic seizures, hypogammaglobulinemia, and mildly impaired gross motor development. Using sequence analysis and deletion/duplication testing, deletion of an entire coding sequence in the SLC2A1 gene was detected. Early introduction of a modified Atkins diet maintained a seizure-free period without antiseizure medications and normal cognitive development in the follow-up period. Our report summarizes the clinical features of GLUT1 syndromes and discusses the importance of early identification and molecular confirmation of GLUT1DS as a treatable metabolic disorder.

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GLUT1 deficiency and other glucose transporter diseases

Acta Endocrinologica ◽

10.1530/eje.0.1500627 ◽

2004 ◽

pp. 627-633 ◽

Cited By ~ 80

Author(s):

JM Pascual ◽

D Wang ◽

B Lecumberri ◽

H Yang ◽

X Mao ◽

...

Keyword(s):

Glucose Transporter ◽

Deficiency Syndrome ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

Metabolic Screening ◽

Genetically Determined ◽

Encoding Genes ◽

Rate Limiting ◽

Carrier Systems ◽

Energy Failure

We review the three genetically determined disorders of glucose transport across cell membranes. Diseases such as glucose-galactose malabsorption, Fanconi-Bickel syndrome and De Vivo disease (GLUT1 deficiency syndrome (GLUT1DS)) arise from heritable mutations in transporter-encoding genes that impair monosaccharide uptake, which becomes rate-limiting in tissues where the transporters serve as the main glucose carrier systems. We focus in greater detail on De Vivo disease as a prototype of a brain energy failure syndrome, for which the greatest pathophysiological detail is known, but which presents the most therapeutic challenges. The study of these diseases illustrates fundamental aspects of energetic metabolism, while providing the basis for their diagnosis by simple metabolic screening and for their treatment by dietary modification.

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GLUT1 deficiency syndrome in a consanguineous Arab family carrying a novel homozygous missense mutation

Neuropediatrics ◽

10.1055/s-0029-1215773 ◽

2008 ◽

Vol 39 (05) ◽

Author(s):

J Klepper ◽

T Ben-Omran ◽

H Scheffer

Keyword(s):

Missense Mutation ◽

Deficiency Syndrome ◽

Homozygous Missense Mutation ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

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Faculty Opinions recommendation of Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12287956.13463054 ◽

2011 ◽

Author(s):

Richard J Naftalin

Keyword(s):

Deficiency Syndrome ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

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Classic Ketogenic Diet and Modified Atkins Diet in SLC2A1 Positive and Negative Patients with Suspected GLUT1 Deficiency Syndrome: A Single Center Analysis of 18 Cases

Nutrients ◽

10.3390/nu13030840 ◽

2021 ◽

Vol 13 (3) ◽

pp. 840

Author(s):

Jana Ruiz Herrero ◽

Elvira Cañedo Villarroya ◽

Luis González Gutiérrez-Solana ◽

Beatriz García Alcolea ◽

Begoña Gómez Fernández ◽

...

Keyword(s):

Movement Disorder ◽

Glucose Transporter ◽

Deficiency Syndrome ◽

Laboratory Assessment ◽

Modified Atkins Diet ◽

Atkins Diet ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

The Impact

Background: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is caused by mutations in the SLC2A1 gene and produces seizures, neurodevelopmental impairment, and movement disorders. Ketogenic dietary therapies (KDT) are the gold standard treatment. Similar symptoms may appear in SLC2A1 negative patients. The purpose is to evaluate the effectiveness of KDT in children with GLUT1DS suspected SLC2A1 (+) and (-), side effects (SE), and the impact on patients nutritional status. Methods: An observational descriptive study was conducted to describe 18 children (January 2009–August 2020). SLC2A1 analysis, seizures, movement disorder, anti-epileptic drugs (AEDS), anthropometry, SE, and laboratory assessment were monitored baseline and at 3, 6, 12, and 24 months after the onset of KDT. Results: 6/18 were SLC2A1(+) and 13/18 had seizures. In these groups, the age for debut of symptoms was higher. The mean time from debut to KDT onset was higher in SLC2A1(+). The modified Atkins diet (MAD) was used in 12 (5 SLC2A1(+)). Movement disorder improved (4/5), and a reduction in seizures >50% compared to baseline was achieved in more than half of the epileptic children throughout the follow-up. No differences in effectiveness were found according to the type of KDT. Early SE occurred in 33%. Long-term SE occurred in 10, 5, 7, and 5 children throughout the follow-up. The most frequent SE were constipation, hypercalciuria, and hyperlipidaemia. No differences in growth were found according to the SLC2A1 mutation or type of KDT. Conclusions: CKD and MAD were effective for SLC2A1 positive and negative patients in our cohort. SE were frequent, but mild. Permanent monitoring should be made to identify SE and nutritional deficits.

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